The invention relates to a process of preparing a compound of the formula 
wherein R1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R2 is hydrogen, alkyl or aralkyl, or salt thereof.
Compounds of Formula I are useful as intermediates in the synthesis of, inter alia, compounds described in WO 97/41102. Compounds described in WO 97/41102 are antagonists of the platelet fibrinogen receptor (gp IIb/IIIa antagonist) and thus are useful for treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina and vaso-occlusive disorders.
Known methods for preparing compounds of Formula I include an asymmetric Michael addition of lithium (R)-N-(trimethylsilyl)-(1)-phenethylamide to ethyl 3-pyridyl acrylate to give the ethyl xcex2-aminoester disclosed in U.S. Pat. No. 5,254,573. This process results in inefficient formation of lithium amide and difficult removal of N-(xcex1-methylbenzyl) group.
J. Org. Chem. vol. 61, p. 2222 (1996) discloses a process wherein the lithium enolate of ethyl acetate is added to an enantiomoric sulfinimine, the product of which is purified by chromatography and deprotected under acidic conditions to afford the xcex2-amino ester in greater than 90% ee. The need for chromatographic purification makes this process unattractive for large-scale production.
WO 98/02410 discloses a process of stereoselective addition of the Reformatsky reagent prepared from t-butylbromoacetate to the enantiomeric imine prepared from 3-pyridine carboxaldehyde and (R)-2-phenylglycinol. Oxidative cleavage of the N-(1-phenyl-2-hydroxy ethyl) group with NaIO4 in ethanol followed by acid hydrolysis affords the enantiomerically pure t-butyl xcex2-amino ester. Use of oxidizing agents makes this process unattractive for large-scale production.
WO 97/41102 discloses enzymatic resolution of the (xc2x1)xcex2-phenylacetamido acid using penicillin amidase to afford the S-acid. This process, which utilizes enzymes, is inefficient and impractical for large scale production.
Thus there exists a need for a process which is compatible with large scale production needs and which achieves acceptable levels of purity and yield.
The invention relates to a process for preparing a compound of the formula 
wherein R1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R2 is hydrogen, alkyl or aralkyl, or salt thereof,
comprising reacting a compound of the formula II 
wherein R1 is as described above and R2xe2x80x2 is alkyl or aralkyl, with a compound of the formula III 
wherein R5 is hydrogen or alkoxy, under conditions of reduced pressure, such that the reaction solution boils at temperatures of between about 40xc2x0 and about 65xc2x0 C., in an inert solvent, which solvent under reduced pressure is capable of azeotropic removal of water, to form the compound of formula IV, 
xe2x80x83reacting the compound of formula IV with hydrogen gas in the presence of a palladium catalyst to form the compound of formula V 
xe2x80x83and reacting the compound of formula V to form the compound of formula Ia or a salt thereof 
wherein R2xe2x80x2 is alkyl or aralkyl.
If desired, compound Ia can further be converted to a compound of formula Ib or a salt thereof, 
wherein R2xe2x80x3 is hydrogen via saponification of the ester.
The process of this invention, as described herein, is advantageous over previously disclosed methods in that it is volume efficient, making it suitable for large scale production.
As used herein, unless otherwise noted, alkyl whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and the like. Unless otherwise noted, xe2x80x9clowerxe2x80x9d when used with alkyl means a carbon-chain composition of 1-4 carbon atoms.
As used herein, unless otherwise noted, xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein alone or as part of a substituent group, unless otherwise noted, xe2x80x9carylxe2x80x9d shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like. The aryl group may be substituted with at least one substituent. Suitable substituents on the aryl group are selected independently from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, lower aralkyl, xe2x80x94NR32, wherein R3 is a lower alkyl; R4CONH, wherein R4 is phenyl or a lower alkyl; and xe2x80x94OC(O)R6 wherein R6 is hydrogen, alkyl or aralkyl.
As used herein, unless otherwise noted, xe2x80x9cheteroarylxe2x80x9d shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from O, N and S or a bicyclic system wherein the monocyclic heteroaryl is fused to an aryl or monocyclic heteroaryl. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, imidazolyl, thienyl, oxazolyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, isoquinolyl, quinolyl, isothiazolyl, and the like. The heteroaryl may be substituted with at least one substituent. Suitable substituents on the heteroaryl group are selected independently from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, lower aralkyl, xe2x80x94NR32, wherein R3 is a lower alkyl; R4CONH, wherein R4 is phenyl or a lower alkyl, and
xe2x80x94OC(O)R6 wherein R6 is hydrogen, alkyl or aralkyl; preferably halogen or lower alkyl. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Preferably, the heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, furanyl and thienyl.
As used herein, unless otherwise noted, xe2x80x9caralkylxe2x80x9d shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like.
As used herein, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine.
As used herein, the notation xe2x80x9c*xe2x80x9d shall denote the presence of a stereogenic center.
Compound of formula IV, because of the presence of a double bond, can exist in either the cis or the trans configuration or as a mixture of the two configurations.
Compound of formula V, because of the presence of two stereogenic centers can exist as any of four diastereomers, or mixture thereof.
As used herein, with respect to reagents and reaction products, the term xe2x80x9cenantiomeric excess or eexe2x80x9d shall mean the excess amount of one enantiomer over another enantiomer. The enantiomeric excess (expressed as a percentage) is calculated as:
[(Amount Enantiomer(1)xe2x88x92Amount Enantiomer(2))/(Total Amount Both Enantiomers)]*100% 
Application of the present invention to a mixture of enantiomers of formula III, substantially free of the R enantiomer, will result in the production of a mixture of enantiomers of formula I, substantially free of the R enantiomer. Similarly, application of the present invention to a mixture of enantiomers of formula III, substantially free of the S enantiomer, will result in the production of a mixture of enantiomers of formula I, substantially free of the S enantiomer. Preferably, the enantiomeric excess of the desired enantiomer of formula III is at least 90 percent ee, more preferably at least 98 percent ee, most preferably 99 percent ee.
In a preferred embodiment of the invention, in the compound of formula I, R1 is phenyl, pyrimidyl, unsubstituted or substituted pyridyl, napthyl or 3,5-dichlorophenyl, more preferably 2-pyridyl, 3-pyridyl or 4-pyridyl, most preferably 3-pyridyl. R2 is preferably lower alkyl, more preferably methyl or ethyl.
The invention relates to a process for preparing a compound of the formula I 
wherein R1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R2 is hydrogen, alkyl or aralkyl, or salt thereof,
comprising reacting a compound of the formula II 
wherein R1 is as described above and R2xe2x80x2 is alkyl or aralkyl, with a compound of the formula III 
wherein R5 is hydrogen or alkoxy, preferably hydrogen or methoxy,
under conditions of reduced pressure, such that the reaction solution boils at temperatures of between about 40xc2x0 and about 65xc2x0 C., in an inert solvent, which solvent under reduced pressure is capable of azeotropic removal of water, to form the compound of formula IV 
xe2x80x83reacting the compound of formula IV with hydrogen gas in the presence of a palladium catalyst to form the compound of formula V 
xe2x80x83and reacting the compound of formula V to form the compound of formula Ia, wherein R2xe2x80x2 is alkyl or aralkyl or a salt thereof. 
If desired, compound Ia can further be converted to a compound of formula Ib or a salt thereof, wherein R2xe2x80x3 is hydrogen via saponification of the ester. 
In accordance with the invention, a compound of formula II, a known compound or compound prepared by known methods, (J. Org. Chem. 1975, 40, 532; J. Org. Chem. 1983, 48, 5006) is reacted with a compound of formula III, a known compound or compound prepared by known methods, (Vestn. Mosk. Univ. Ser2: Khim. 1977, 18, 446; CAN 88:62074) in the presence of an acid, preferably a carboxylic acid, most preferably acetic acid, under vacuum, preferably the vacuum is adjusted so that the boiling point of the mixture is between about 40xc2x0 and about 65xc2x0 C. in an inert solvent, which solvent under reduced pressure is capable of azeotropic removal of water, such as xylene, heptane or toluene, preferably toluene, to form the compound of formula IV.
When the process is applied to a compound of formula II wherein R1 is a nitrogen containing heteroaryl, the reaction is carried out in the presence of at least two equivalents of a carboxylic acid, preferably acetic acid.
Preferably, when R1 is a N containing heteroaryl, the reaction solution is further washed with an aqueous base such as sodium bicarbonate, sodium carbonate and the like, to remove excess acid.
The compound of formula IV is reacted with hydrogen gas in the presence of a palladium catalyst such as palladium hydroxide on carbon, palladium on carbon and the like, preferably at least 10 weight percent of 20 percent palladium hydroxide on carbon, preferably under atmospheric pressure, in an alcohol solvent, such as lower alkyl alcohol, preferably methanol, preferably at from about 0xc2x0 to about 40xc2x0 C., most preferably at room temperature, to form the corresponding compound of formula V.
The desired diastereomer of formula V is preferably isolated by conventional methods known to one skilled in the art, such as recrystallization from an organic solvent such as ethyl acetate, methanol, methyl-t-butyl ether and the like, HPLC or flash chromatography.
The compound of formula V is reacted in an acid, such as acetic acid, formic acid, propionic acid, trifluoroacetic acid (TFA), hydrochloric acid or mixtures thereof, preferably formic acid, preferably in the presence of a hydrosilane such as di lower alkyl silane or tri lower alkyl silane, preferably triethylsilane, at a temperature of in the range of about 40xc2x0 to about 100xc2x0 C., preferably at about 80xc2x0 to about 100xc2x0 C., to form the corresponding compound of formula Ia, wherein R2xe2x80x2 is alkyl or aralkyl.
If desired, a compound of formula Ia or a salt thereof, wherein R2xe2x80x2 is alkyl or aralkyl, can further be converted to a compound of formula Ib or a salt thereof, wherein R2xe2x80x3 is hydrogen, via saponification of the ester by conventional methods, such as reacting the compound of formula Ia or a salt thereof with lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF) or methanol.
The following examples describe the invention in greater detail and are intended to illustrate the invention, but not to limit it.